Project 2: Mechanochemical Mechanisms and Vulnerabilities of Individual and Collective Organ-Preferential Metastasis In Vivo

项目2：体内个体和集体器官优先转移的机械化学机制和脆弱性

基本信息

批准号：
10490290
负责人：
Peter Friedl
金额：
$ 36.9万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10490290
关键词：
Actomyosin Address Adherens Junction Adhesions Basement membrane Blood Circulation Blood Vessels Breast Cancer Cell CD44 gene Cathepsins Cell Cycle Arrest Cell Death Cell Nucleus Cell Survival Cell-Cell Adhesion Cells Cellular Stress Chromatin Chromatin Structure Clinical Coagulation Process Computer Models Cytometry Cytoplasm Data Distant Distant Metastasis Down-Regulation Endothelium Engineering Environment Extravasation Growth Individual Intercellular Junctions Intervention Kinetics Lamin Type A Liquid substance Liver Matrix Metalloproteinases Mechanical Stress Mechanics Mediating Melanoma Cell Metastatic Neoplasm to the Liver Metastatic Skin Cancer Microanatomy Modeling Molecular Molecular Conformation Molecular Target Monitor Movement Mus Neoplasm Circulating Cells Neoplasm Metastasis Nuclear Organ Outcome Pathway interactions Peptide Hydrolases Probability Process Regulation Scheme Secure Site Skin Solid Stress Survival Rate System Testing Tissue imaging Tissues Variant Vascular remodeling base cancer cell cell motility coping early onset experience fitness in silico in vivo in vivo Model intravital microscopy live cell microscopy mechanical properties mouse model multiphoton microscopy neoplastic cell novel prevent programs response shear stress success tissue stress transcriptomics triple-negative invasive breast carcinoma vascular bed

项目摘要

Project 2: SUMMARY Organ colonization and survival of circulating tumor cells (CTCs) depends on a response program in tumor cells (TCs), termed mechano-adaptation, to cope with mechanical and molecular stresses on the cytoplasm and nucleus experienced during intravascular arrest and extravasation. The strength and duration of mechanical stress differs in vascular beds among organs, such as liver and skin, and further differs between individual-cell and collective organ colonization. Molecular systems implicated in the mechano-adaptation of CTCs include coordinated cell-cell adhesions, cytoskeletal contractility, protease systems and deformation or the nucleus, which cooperate to secure multistep movement into the secondary site and TC survival. We hypothesize that successful metastasis in vivo depends on an adaptive interplay between the mechanical and molecular intra- and perivascular stresses present at distant site and the coping ability of CTCs to overcome these stresses. By coordinated cell-cell adhesion, cytoskeletal contractility, deformation of the nucleus, and protease systems we predict that mechano-adaptation secures individual-cell and collective TC survival and further mediates lasting reprogramming towards growth or dormancy. Consequently, we anticipate that interfering with cell mechanical adaptation strategies will increase cell stress, support CTC death and diminish metastatic organ colonization. By combining intravital microscopy in mouse models, computational modeling (Core A) and transcriptomic and chromatin structure analyses (Core B), we will address the rate-limiting steps of single-cell and collective organ colonization of triple-negative breast cancer and melanoma cells to skin and liver. In Aim 1 we will examine the mechanisms of collective and single-cell organ colonization and metastatic outcomes, by interfering with adherens junctions (p120-catenin) and intravascular coagulation. In Aim 2, we will identify the rate-limiting steps of cytoskeletal and nuclear mechanics and the ability to remodel the vascular wall during single-cell and collective organ colonization. Targeted interference with CD44-mediated adhesion to perivascular substrate, actomyosin contractility, nuclear deformability by lamin A/C expression variation and the ability to reorganize the basement membrane will be performed. In Aim 3, we will identify the molecular responses underlying stress-induced mechano- adaptation and associated effects on nuclear chromatin conformation, using transcriptomic and ultrastructural analyses combined with computational modeling. Identified key pathways implicated in mediating mechano- adaptation and TC survival, cell cycle arrest (dormancy) and outgrowth will be inhibited by combined molecular interference to limit TC survival and both single-cell and collective metastasis. This project will deliver an integrated view on cell migration, molecular reprogramming, fate decisions, and reveal potential intervention points to enhance tumor cell elimination in transit.

项目 2：总结循环肿瘤细胞 (CTC) 的器官定植和存活取决于肿瘤的反应程序细胞（TC），称为机械适应，以应对细胞质上的机械和分子压力以及在血管内停滞和外渗过程中经历的细胞核。强度和持续时间不同器官（例如肝脏和皮肤）的血管床的机械应力不同，并且不同器官之间的机械应力也不同。个体细胞和集体器官定植。分子系统涉及机械适应 CTC 包括协调的细胞间粘附、细胞骨架收缩性、蛋白酶系统和变形或细胞核，它们合作以确保多步移动到次要位点和 TC 存活。我们假设体内成功的转移取决于机械力之间的适应性相互作用和远处部位存在的血管内和血管周围分子应力以及 CTC 的应对能力克服这些压力。通过协调细胞间粘附、细胞骨架收缩性、细胞变形细胞核和蛋白酶系统，我们预测机械适应可确保个体细胞和集体 TC 存活并进一步介导持久的重编程以实现生长或休眠。因此，我们预计干扰细胞机械适应策略会增加细胞应激，支持 CTC 死亡并减少转移器官定植。通过在小鼠模型中结合活体显微镜检查，计算建模（核心 A）以及转录组和染色质结构分析（核心 B），我们将解决三阴性乳腺癌单细胞和集体器官定植的限速步骤以及皮肤和肝脏的黑色素瘤细胞。在目标 1 中，我们将研究集体和单细胞的机制通过干扰粘附连接（p120-连环蛋白）和血管内凝血。在目标 2 中，我们将确定细胞骨架和核的限速步骤。单细胞和集体器官定植期间的力学和重塑血管壁的能力。靶向干扰 CD44 介导的血管周围基质粘附、肌动球蛋白收缩性、由核纤层蛋白 A/C 表达变化引起的核变形性和重组基底膜的能力将被执行。在目标 3 中，我们将确定应力诱导机械作用下的分子反应利用转录组学和超微结构研究对核染色质构象的适应和相关影响分析与计算建模相结合。确定了介导机械作用的关键途径适应和 TC 存活、细胞周期停滞（休眠）和生长将受到组合的抑制分子干扰限制 TC 存活以及单细胞和集体转移。该项目将提供关于细胞迁移、分子重编程、命运决定的综合观点，并揭示潜力干预点可增强转运过程中肿瘤细胞的消除。